CN104211638A - Fatty amino substituted graveoline derivative, its preparation and its application as anti-Alzheimer's disease medicine - Google Patents

Fatty amino substituted graveoline derivative, its preparation and its application as anti-Alzheimer's disease medicine Download PDF

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CN104211638A
CN104211638A CN201410400128.7A CN201410400128A CN104211638A CN 104211638 A CN104211638 A CN 104211638A CN 201410400128 A CN201410400128 A CN 201410400128A CN 104211638 A CN104211638 A CN 104211638A
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graveoline
preparation
analog derivative
derivative
alzheimer
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李增
常俊
芦宝静
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4

Abstract

The invention belongs to the fields of pharmaceutical chemistry and pharmaceutical therapeutics, and discloses a fatty amino substituted graveoline derivative, its preparation and its application as an Alzheimer's disease treatment medicine. Researches prove that the fatty amino substituted graveoline derivative has very strong inhibition and very good inhibition selectivity on acetylcholinesterase, and the acetylcholinesterase inhibition ability of the derivative is above 1200 times higher than the butyrylcholine esterase inhibition activity of the derivative. The compound can be developed to form medicines for treating the Alzheimer's disease.

Description

The graveoline analog derivative that a kind of fat amido replaces and preparation thereof and as the application in the medicine of anti-alzheimer's disease
Technical field
The invention belongs to pharmaceutical chemistry and pharmacotherapeutics field, be specifically related to a kind of fat amido replace graveoline analog derivative and as prepare anti-alzheimer's disease medicine in application.
Background technology
Along with improving constantly of people's living standard, world population ages's phenomenon is day by day serious, and geriatric disease has become the focus that society is paid close attention to.Along with the aging of population, the senile dementia of the Alzheimer's disease being feature based on Progressive symmetric erythrokeratodermia hypomnesis and cognitive disorder (Alzheimer's Disease AD) oneself become the third-largest disease threatening the elderly's life after cardiovascular and cerebrovascular diseases, malignant tumour.AD not only seriously jeopardizes the health of the mankind especially the elderly, and brings heavy spirit and economical load to family numbers of patients, for society brings huge crisis, causes tremendous influence to economy.The Alzheimer's disease organized by Alzheimer's disease federation in July, 2006 and associated disorders symptom International Year can be gone up, Sweden researchist announce that the whole world is at present used for the treatment of alzheimer's disease every year every directly and overhead cost own close to 2,500 hundred million dollars.Therefore, accelerate the research of AD pathogenesis and find effective AD medicine and have important medical science and social effect, oneself is through becoming the hot-point and frontier field that international the world of medicine attractes attention.
AChE inhibitor based on cholinergic hypothesis design is that current clinical treatment AD uses maximum medicines, but result for the treatment of is unsatisfactory, study and find novel effectively for the medicine of AD, comprise the research strategy to improve the anti-AD medicine of dibit point for the purpose of activity and selectivity, by two, identical or different pharmacophore is connected by certain mode, obtain bimolecular body or heterozygote, can be combined with the centers catalyse site of AChE and PAS simultaneously, thus raising inhibit activities.Paid close attention to widely in the design and development of AChE inhibitor.
The biological function of acetylcholinesterase is more clearly, but the biological function of the butyrylcholine esterase of its same enzyme system is still not very clear so far.But there are some evidences to show, the activity of BuChE possibility Ahl tribulus sea silent sickness pathogeny is relevant, so there is scholar to propose the hypothesis of non-selective suppression Pseudocholinesterase, think that can suppress AChE that the nonselective anticholinesterase of BuChE can be suppressed again to compare optionally acetylcholinesterase depressant is more of value to the treatment of Alzheimer's disease.But be mainly present in peripheral nervous system due to BuChE, suppress BuChE can produce the side effect of Pseudocholinesterase peripheral nerve.The dose effect curve trembled (centre effect) and salivate (periphery effect) shows, the acetylcholinesterase depressant E2020 of highly selective can suppress again the tacrine of BuChE to have more excellent therapeutic index than suppressing AChE.In addition, report recently AD patients' neural cynapse find the activity of BuChE decline to some extent.These results of study are pointed out, in AD medicament research and development, highly selective, highly active acetylcholinesterase depressant are more promising.
Summary of the invention
For achieving the above object, the invention provides the graveoline analog derivative that a kind of fat amido replaces.
Another object of the present invention is the preparation method of the graveoline analog derivative providing this fat amido to replace.
The graveoline analog derivative that a further object of the invention is to provide this fat amido to replace is as the application of anti-alzheimer disease drug.
The present invention is achieved by the following technical solutions:
The graveoline analog derivative that fat amido replaces, is characterized in that structural formula is:
Wherein n=2,3; R represents the one in dimethylamino, diethylin, pyrryl, piperidyl, morpholinyl, 1-methylpiperazine base.
The preparation method of the graveoline analog derivative that described fat amido replaces, is characterized in that:
Preparation method comprises the following steps:
(1) by graveoline analogue under weak base effect, methylate is obtained after heated and stirred with the methyl iodide of 3-5 times amount
(2) after step (1) products therefrom being carried out bromination reaction, then mix with various aliphatic amide, ammoxidation obtains the graveoline analog derivative that end product fat amido replaces wherein n=2,3, R is the one in dimethylamino, diethylin, pyrryl, piperidyl, morpholinyl, 1-methylpiperazine base.
The preparation method of the graveoline analog derivative that described fat amido replaces, is characterized in that: in step (1), weak base is K 2cO 3, heated and stirred temperature is 60-65 DEG C, and churning time is 3-5 hour, and reaction solvent is DMF.The preparation method of the graveoline analog derivative that described fat amido replaces, it is characterized in that in step (2), bromination reaction reagent is NBS, catalyzer is benzoyl peroxide, and solvent is CCl 4; Ammoxidation temperature is room temperature.
The application of the graveoline analog derivative that described fat amido replaces, is characterized in that as the application in the medicine of the anti-alzheimer's disease of preparation.
Described application, described medicine is injection, tablet, pill, capsule, suspension agent or emulsion.
The preparation method of the graveoline analog derivative that this fat amido of the present invention replaces, principal synthetic routes is:
Its concrete steps are:
(1) by graveoline analogue dMF solvent with 15 times amount, adds the CH of 3-5 times amount 3i, at K 2cO 3effect under 60-65 DEG C stir after 3-5 hour, cooling, pressure reducing and steaming DMF, obtains methylate after silica gel column chromatography
(2) above-mentioned methylate is dissolved in CCl 4in, add the NBS of equimolar amount and the benzoyl peroxide N of catalytic amount 2reflux under protection 5h, termination reaction, cooling, and distillation, is dissolved in the addition of C H after drying 2cl 2, add the aliphatic amide of 5 times amount subsequently, stirred overnight at room temperature, stopped reaction, dry, neutral alumina column chromatography, obtains the graveoline analog derivative that end product fat amido replaces wherein n=2,3, R is dimethylamino, diethylin, pyrryl, piperidyl, morpholinyl, 1-methylpiperazine base.Compared with prior art, the present invention has following beneficial effect:
The present invention passes through the Inhibition test of external acetylcholinesterase and butyrylcholine esterase, prove that the graveoline analog derivative that fat amido of the present invention replaces has stronger inhibit activities and higher selectivity to acetylcholinesterase, can apply as acetylcholine esterase inhibitor medication.Show that derivative of the present invention can be used for preparing the medicine for the treatment of alzheimer's disease.
The invention discloses a kind of fat amido replace graveoline analog derivative and preparation and as treat alzheimer's disease medicine in application.Research proves, the graveoline analog derivative that fat amido involved in the present invention replaces has very strong rejection to acetylcholinesterase and well suppresses selectivity, and it exceeds more than 1200 times to the inhibit activities of the rejection ability comparison butyrylcholine esterase of acetylcholinesterase.Show that this compounds can develop into the medicine for the treatment of Alzheimer's disease (Alzheimer ' sdisease).
Concrete embodiment:
The present invention is further described below in conjunction with specific embodiment.Unless stated otherwise, the present invention adopts reagent, equipment and method are conventional commercial reagent, equipment and the conventional method used of the art.
Embodiment one: the synthesis of compound 3
By compound 2, i.e. graveoline analogue (4.60g, about 0.02mol) is dissolved in 100mL dry DMF, adds the K of 2 times of molar weights 2cO 3, drip 3.00mLCH subsequently 3i, is heated to 62 DEG C under nitrogen protection, isothermal reaction 5h.Termination reaction, pressure reducing and steaming DMF, obtains yellow raw product.With 300mL acetic acid ethyl dissolution yellow solid, distilled water wash (50mL × 3), organic phase has Calcium Chloride Powder Anhydrous dry, filters, distillation, dry yellow solid.Brownish-yellow powder solid 3 (1.42g) is obtained, productive rate 28% with purification by silica gel column chromatography [V (sherwood oil): V (ethyl acetate)=1:1]. 1H?NMR(400MHz,CDCl 3):δ8.50(d,J＝8.0Hz,1H),7.71(t,J＝8.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.42(t,J＝7.8Hz,1H),7.30(s,4H),6.30(s,1H),3.61(s,3H),2.44(s,3H).APCI-MS?m/z:250.1[M+1] +。
The chemical formula of compound 3 is as follows:
Embodiment two: the synthesis of compound 5a
Compound 3 (0.8g, 3.2mmol), NBS (0.56g, 3.2mmol), benzoyl peroxide (0.04g) is dissolved in 30mLCCl 4in, N 2reflux under protection 5h.Termination reaction, suction filtration after cooling reaction solution, filtrate decompression is distilled, and obtains rough yellow-brown solid compound 4.Get the raw product 0.5g of compound 4, be dissolved into 10mL CH 2cl 2in, drip 3mL N, N-dimethyl-ethylenediamine, stirred overnight at room temperature.Stopped reaction, adds 60mL CH in reaction solution 2cl 2, use saturated common salt water washing (40mL × 3) subsequently, organic phase is dry with Calcium Chloride Powder Anhydrous, filters, the light yellow oil of filtrate decompression distillation.Faint yellow solid 5a is obtained with neutral alumina column chromatography [V (trichloromethane): V (methyl alcohol)=25:1]. 1H?NMR(400MHz,CDCl 3):δ7.96(dd,J＝7.5,1.4Hz,1H),7.68–7.55(m,3H),7.32(d,J＝7.4Hz,2H),7.08(td,J＝7.6,1.6Hz,1H),6.90(dd,J＝7.6,1.4Hz,1H),6.85(s,1H)6.45(s,1H),3.92(s,2H),3.52(s,3H),2.63(t,2H),2.54(t,2H),2.32(s,6H).APCI-MS?m/z:335.2[M+1] +。
The chemical formula of compound 5a is as follows:
Embodiment three: the synthesis of compound 5b
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with N, N-diethyl ethylenediamine, obtains faint yellow solid 5b. 1H?NMR(400MHz,CDCl 3):δ8.01(dd,J＝7.6,1.4Hz,1H),7.67(td,J＝7.6,1.4Hz,1H),7.62(d,J＝7.6Hz,2H),7.32(d,J＝7.6Hz,2H),7.09(td,J＝7.6,1.4Hz,1H),6.91(dd,J＝7.6,1.6Hz,1H),6.87(s,1H),6.46(s,1H),3.92(d,J＝6.2Hz,2H),3.49(s,3H),2.90(q,J＝6.4Hz,2H),2.66(t,2H),2.51(m,4H),1.16(t,6H).APCI-MS?m/z:363.1[M+1] +。
The chemical formula of compound 5b is as follows:
Embodiment four: the synthesis of compound 5c
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with N-(2-aminoethyl) tetramethyleneimine, obtains faint yellow solid 5c. 1H?NMR(400MHz,CDCl 3):δ8.13(dd,J＝7.5,1.4Hz,1H),7.71–7.60(m,3H),7.31(d,J＝7.4Hz,2H),7.12(td,J＝7.6,1.6Hz,1H),6.93(dd,J＝7.6,1.4Hz,1H),6.86(s,1H),6.45(s,1H),3.92(s,2H),3.52(s,3H),3.03(t,2H),2.64(t,2H),2.56-2.43(t,4H),1.66(m,4H).APCI-MS?m/z:361.1[M+1] +。
The chemical formula of compound 5c is as follows:
Embodiment five: the synthesis of compound 5d
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with 1-(2-aminoethyl) piperidines, obtains faint yellow solid 5d. 1H?NMR(400MHz,CDCl 3):δ8.04(dd,J＝6.8,1.4Hz,1H),7.70–7.62(m,3H),7.35(d,J＝7.4Hz,2H),7.14(td,J＝7.4,1.6Hz,1H),6.98(dd,J＝7.4,1.4Hz,1H),6.83(s,1H),6.45(s,1H),3.92(s,2H),3.55(s,3H),2.69(t,J＝5.4Hz,2H),2.66(t,2H),2.36(t,J＝5.4Hz,4H),1.64(m,4H),1.52(m,2H).APCI-MS?m/z:375.2[M+1] +。
The chemical formula of compound 5d is as follows:
Embodiment six: the synthesis of compound 5e
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with 2-aminoethyl morpholine, obtains faint yellow solid 5e. 1H?NMR(400MHz,CDCl 3):δ8.14(dd,J＝7.6,1.4Hz,1H),7.69–7.59(m,3H),7.36(d,J＝7.6Hz,2H),7.11(td,J＝7.4,1.6Hz,1H),6.94(dd,J＝7.5,1.4Hz,1H),6.77(s,1H),6.42(s,1H),3.92(s,2H),3.54(s,3H),3.18(t,J＝4.8Hz,2H),2.58(t,2H),2.16(t,4H),1.83(t,4H).APCI-MS?m/z:377.2[M+1] +。
The chemical formula of compound 5e is as follows:
Embodiment seven: the synthesis of compound 5f
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with 1-(2-aminoethyl)-4-methylpiperazine, obtains faint yellow solid 5f. 1H?NMR(400MHz,CDCl 3):δ8.21(dd,J＝7.6,1.4Hz,1H),7.73–7.58(m,3H),7.36(d,J＝7.6Hz,2H),7.14(td,J＝7.6,1.6Hz,1H),6.96(dd,J＝7.6,1.4Hz,1H),6.86(s,1H),6.53(s,1H),3.92(s,2H),3.58(s,3H),2.65(m,2H),2.58(t,J＝4.8Hz,2H),2.52(dt,J＝8.2,2.8Hz,4H),2.38–2.31(m,4H),2.22(s,3H).APCI-MS?m/z:390.2[M+1] +。
The chemical formula of compound 5f is as follows:
Embodiment eight: the synthesis of compound 5g
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with N, N-dimethylated propyl diethylenetriamine, obtains faint yellow solid 5g. 1H?NMR(400MHz,CDCl 3):δ8.24(dd,J＝7.6,1.4Hz,1H),7.95–7.64(m,3H),7.46(d,J＝7.6Hz,2H),7.22(td,J＝7.6,1.6Hz,1H),7.08(dd,J＝7.6,1.4Hz,1H),7.01(s,1H),6.50(s,1H),3.92(s,2H),3.54(s,3H),2.61(t,J＝7.6Hz,2H),2.50(t,J＝7.6Hz,2H),2.27(s,6H),1.42(m,2H).APCI-MS?m/z:349.2[M+1] +。
The chemical formula of compound 5g is as follows:
Embodiment nine: the synthesis of compound 5h
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with N, N-diethyl propyldiamine, obtains faint yellow solid 5h. 1H?NMR(400MHz,CDCl 3):δ8.22(dd,J＝7.6,1.4Hz,1H),7.96–7.66(m,3H),7.48(d,J＝7.6Hz,2H),7.24(td,J＝7.6,1.6Hz,1H),7.12(dd,J＝7.6,1.4Hz,1H),7.02(s,1H),6.44(s,1H),3.92(s,2H),3.51(s,3H),3.07(q,J＝6.4Hz,2H),2.82(q,J＝6.4Hz,2H),2.62(m,4H),1.42(m,2H),1.32(t,J＝6.2Hz,6H).APCI-MSm/z:377.2[M+1] +。
The chemical formula of compound 5h is as follows:
Embodiment ten: the synthesis of compound 5i
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with 1-(3-aminopropyl) tetramethyleneimine, obtains faint yellow solid 5i. 1H?NMR(400MHz,CDCl 3):δ8.31(dd,J＝7.6,1.4Hz,1H),7.89–7.64(m,3H),7.48(d,J＝7.6Hz,2H),7.32(td,J＝7.6,1.6Hz,1H),6.99(dd,J＝7.6,1.4Hz,1H),6.88(s,1H),6.45(s,1H),3.94(s,2H),3.52(s,3H),3.07(t,2H),2.62(t,J＝7.6Hz,2H),2.48(t,2H),2.32(m,4H),1.66(m,4H).APCI-MS?m/z:375.2[M+1] +。
The chemical formula of compound 5i is as follows:
Embodiment 11: the synthesis of compound 5j
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with 1-(3-aminopropyl) piperidines, obtains faint yellow solid 5j. 1H?NMR(400MHz,CDCl 3):δ8.26(dd,J＝7.4,1.4Hz,1H),7.65(ddd,J＝10.8,8.2,4.4Hz,3H),7.32(d,J＝7.5Hz,2H),7.28(td,J＝7.6,1.6Hz,1H),7.16(dd,J＝7.6,1.4Hz,1H),6.88(s,1H).6.45(s,1H),3.97(s,2H),3.53(s,3H),3.14(t,J＝5.4Hz,2H),2.60(dd,J＝16.0,7.8Hz,2H),2.37(dt,J＝10.7,6.5Hz,4H),1.67–1.60(m,6H),1.52(m,2H).APCI-MS?m/z:389.2[M+1] +。
The chemical formula of compound 5j is as follows:
Embodiment 12: the synthesis of compound 5k
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with N-amine propylmorpholin, obtains faint yellow solid 5k. 1H?NMR(400MHz,CDCl 3):δ8.25(dd,J＝7.6,1.4Hz,1H),7.68–7.55(m,3H),7.32(d,J＝7.6Hz,2H),7.17(td,J＝7.6,1.4Hz,1H),6.99(dd,J＝7.4,1.5Hz,1H),6.85(s,1H),6.50(s,1H),3.95(s,2H),3.49(s,3H),3.27(t,2H),2.64(t,J＝5.4Hz,2H),2.56(t,J＝4.8Hz,4H),2.25(t,J＝4.7Hz,4H),1.65(m,2H).APCI-MS?m/z:391.2[M+1] +。
The chemical formula of compound 5k is as follows:
Embodiment 13: the synthesis of compound 5l
Method is with embodiment two, and difference replaces N, N-dimethyl-ethylenediamine with 1-(3-aminopropyl)-4-methylpiperazine, obtains faint yellow solid 5l. 1H?NMR(400MHz,CDCl 3):δ8.21(dd,J＝7.6,1.4Hz,1H),7.68–7.55(m,3H),7.44(d,J＝7.6Hz,2H),7.23(td,J＝7.6,1.6Hz,1H),7.14(dd,J＝7.6,1.4Hz,1H),7.02(s,1H),6.45(s,1H),3.98(s,2H),3.50(s,3H),3.03(dt,J＝10.2,7.8Hz,2H),2.58(t,J＝4.8Hz,2H),2.54(t,4H),2.35(dq,J＝9.8,5.0Hz,4H),2.22(s,3H),1.66(m,2H).APCI-MS?m/z:404.2[M+1] +。
The chemical formula of compound 5l is as follows:
Embodiment 9: test compounds is to the restraining effect (BiochemicalPharmacology1961,7,88-95.) of acetylcholinesterase and butyrylcholine esterase
Result IC 50value represents, using Tacrine as positive control.All tests are all carried out in the long microplate reader of PowerWaveXS2 type all-wave, measure under the condition of 37 DEG C.Data analysis utilizes software Origin process.
Experimental procedure:
1) preparation of compound solution:
Test compounds is made into 10mM concentration (solvent: DMSO) ,-20 DEG C of cryogenic refrigerators are preserved, and are diluted to desired concn when making with phosphate buffered saline buffer (0.1mol/L, pH8.0).
2) preparation of enzyme storing solution:
Acetylcholinesterase (E.C.3.1.1.7, from electric ell.) and butyrylcholine esterase (E.C.3.1.1.8, from equine serum) is bought from Sigma company; Acetylcholinesterase storing solution is formulated as 0.1mg/ml, and butyrylcholine esterase storing solution is formulated as 0.2mg/ml.
3) preparation of Substrate stock liquid:
Acetylthiocholine (Acetylthiocholine, ATC) and sulfo-BuCh (Butylthiocholine, BTC) is bought from Sigma company; Take a certain amount of ATC or BTC, be mixed with the solution of 0.01mol/L with phosphate buffer soln (0.1mol/L, pH8.0), for subsequent use.
4) preparation of developer storing solution:
The developer DTNB bought from Sigma company is mixed with 0.01mol/L with phosphate buffer soln (0.1mol/L, pH8.0), and 4 DEG C of shadings are preserved, for subsequent use.
5) compound enzyme level ability detects:
Each compound chooses 6 hole tests in 96 orifice plates; Add 10 μ L enzyme solution respectively; 0,5,10,20,35,50 μ L testing compound solutions; Adding 0.1mol/LpH8.0 phosphate buffer solution makes cumulative volume be 100 μ L.
In 37 DEG C of long microplate reader of all-wave, hatch 15min, add the mixed solution totally 100 μ L of 10 μ LATC solution (or BTC), 10 μ LDTNB solution and 80 μ L phosphate buffer solutions immediately, scan 2min at λ=412nm and measure absorbancy change.
6) result calculates:
The calculating of IC50 value: absorbancy change (slope) recorded during not add inhibitor is 100 unit of activity (Acontrol), enzyme activity=(absorbancy adding inhibitor change/does not add the absorbancy change of inhibitor) × 100, when enzyme activity reaches 50, be the IC of inhibitor 50value.
Experimental result is the mean value of three independent experiments.
7) experimental result:
Table 1 compound 5a-5l and Tacrine is to acetylcholinesterase and the inhibiting IC of butyrylcholine esterase 50value and suppression selectivity
ato the selectivity=IC of acetylcholinesterase 50(butyrylcholine esterase)/IC 50(acetylcholinesterase)
8) conclusion: find that all derivatives all have good inhibit activities to acetylcholinesterase from table 1, activity reaches 0.6 ~ 9.3nM, and more weak to the inhibit activities of butyrylcholine esterase, higher to the selectivity of acetylcholinesterase, selectivity scope reaches 755 ~ 3225.Compound 5l shows best inhibiting activity of acetylcholinesterase, (IC50 is 0.60nM), has best acetylcholine ester enzyme level selectivity (3092) simultaneously.

Claims (6)

1. a graveoline analog derivative for fat amido replacement, is characterized in that structural formula is:
Wherein n=2,3; R represents the one in dimethylamino, diethylin, pyrryl, piperidyl, morpholinyl, 1-methylpiperazine base.
2. a preparation method for the graveoline analog derivative of fat amido replacement as claimed in claim 1, is characterized in that:
Preparation method comprises the following steps:
(1) by graveoline analogue under weak base effect, methylate is obtained after heated and stirred with the methyl iodide of 3-5 times amount
(2) after step (1) products therefrom being carried out bromination reaction, then mix with various aliphatic amide, ammoxidation obtains the graveoline analog derivative that end product fat amido replaces wherein n=2,3, R is the one in dimethylamino, diethylin, pyrryl, piperidyl, morpholinyl, 1-methylpiperazine base.
3. a preparation method for the graveoline analog derivative of fat amido replacement as claimed in claim 2, is characterized in that: in step (1), weak base is K 2cO 3, heated and stirred temperature is 60-65 DEG C, and churning time is 3-5 hour, and reaction solvent is DMF.
4. a preparation method for the graveoline analog derivative of fat amido replacement as claimed in claim 2, it is characterized in that in step (2), bromination reaction reagent is NBS, catalyzer is benzoyl peroxide, and solvent is CCl 4; Ammoxidation temperature is room temperature.
5. an application for the graveoline analog derivative of fat amido replacement as claimed in claim 1, is characterized in that as the application in the medicine of the anti-alzheimer's disease of preparation.
6. the application as described in claim 5 or 6, described medicine is injection, tablet, pill, capsule, suspension agent or emulsion.
CN201410400128.7A 2014-08-13 2014-08-13 Fatty amino substituted graveoline derivative, its preparation and its application as anti-Alzheimer's disease medicine Pending CN104211638A (en)

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Application publication date: 20141217